The control of all biological processes results from a balance between various positive and negative-acting factors which interact with DNA regulatory elements and with each other. These protein factors play a critical role in controlling the expression of proteins, and thus are critical to both normal and pathological processes. Understanding these protein factors and how they modulate gene expression is key to strategies for the development of agents to control disease initiation and progression.
A number of these important trans-acting regulatory proteins have been described in the literature and have been demonstrated to play a role in pathological processes. One such factor is NF-kB, a member of the Rel family of eukaryotic transcription factors. The Rel family of proteins controls a wide variety of cellular responses. For example, they are key regulatory molecules for signal-responsive induction of gene expression, host-defensive responses, and growth responses. The ability to specifically modulate the binding of NF-kB and other members of the Rel family would be useful for the treatment of a wide variety of conditions ranging from septic shock, graft vs host reactions, acute inflammatory conditions, systemic inflammatory responses, acute phase responses, vascular coagulation, ischemic reperfusion injury, atherosclerosis, HIV infection and cancer.
Another transcription factor of importance is BEF-1, a member of the NF-1 family of transcriptional regulators. BEF-1 was first identified as a transcriptional repressor within the enhancer of human BK virus. The binding site for this ubiquitous transcription factor is present in the regulatory regions of a number of human genes. For example, BEF-1 has been shown to control the expression of human apolipoprotein E, a major constituent of plasma lipoprotein that functions in lipid transport and redistribution (reverse cholesterol transport). ApoE also probably plays an important role in inhibiting the development and/or progression of atherosclerosis. Both the level and binding activity of BEF-1 have been shown to be regulated via intracellular signaling, as demonstrated by effects mediated through the viral oncogene Ela, cytokines and also through tyrosine phosphorylation.
We have found that BEF-1 binding sites can overlap with NF-kB binding sites (e.g.., vascular adhesion molecule-1: VCAM-1). Conversely, BEF-1 binding sites such as in the apoE promoter can bind Rel proteins. Thus, both BEF-1 and NF-kB may compete for binding at the same site. Furthermore, compounds that modulate the levels of BEF-1 activity may be effective not only in modulating genes controlled by BEF-1, but those controlled by NF-kB as well.
This invention provides methods for modulating NF-kB transcription factor comprising administering to a human in need thereof an effective amount of a compound of formula I 
wherein
R1 and R3 are independently hydrogen, 
xe2x80x83wherein Ar is optionally substituted phenyl;
R2 is selected from the group consisting of pyrrolidino, hexamethyleneimino, and piperidino; and pharmaceutically acceptable salts and solvates thereof.